For many patients with small cell lung cancer (SCLC) for whom expected survival may be measured in months or even weeks, the quality of their remaining life may be as important as or even more important than a small extension of survival. Therefore, for such patients and their doctors to be fully informed about the likely impact of the various treatment options on their daily lives, the assessment of quality of life (QL) should be a key component of all randomized trials in SCLC. A quick review of the literature to try to assess the level of such reporting, however, indicated that of 128 articles identified on MEDLINE as having "randomized" (or "randomised") and "small cell lung cancer" in their titles, only 20 referred to QL, symptoms, or palliation in their abstracts. Although it is recognized that the assessment of QL can be a major undertaking that requires commitment and enthusiasm from all participants, in this particular disease, the failure of most randomized trials to do so is worrying.
Bone marrow transplantation, hydroxyurea therapy in children and in patients with sickling disorders other than sickle cell anemia, and prophylactic transfusion for prevention of stroke in children are currently being evaluated as treatments for patients with sickle cell disease. Long-term complications of each of these treatments are incompletely understood. Attempts to inhibit sickling by lowering intracellular hemoglobin concentration are still in progress. Combinations of therapeutic agents with different modes of action, and development of more effective treatment schedules, may further improve the outlook of patients with sickling disorders.
Interferons are polypeptides with a broad range of in vivo effects that have shown efficacy in cutaneous T-cell lymphoma (CTCL). Particularly useful is alfa interferon (IFN) which, as a single agent, has shown partial remission rates of > 50% and complete responses of > 20%. Side-effects are predictable, generally well tolerated and dose-related. The efficacy of IFN has increased with combination therapy without any significant increase in attendant side-effects. An update on the specifics of the different IFN subtypes, their inherent biologic activity, pharmacokinetics, efficacy and safety in CTCL is presented in this paper.
Based on the frequent aberration in cell cycle regulatory pathways in human cancer by cdk hyperactivation, novel ATP competitive cdk inhibitors are being developed. The first two tested in clinical trials, flavopiridol and UCN-01, showed promising results with evidence of antitumor activity and plasma concentrations sufficient to inhibit cdk-related functions. Best schedule to be administered, combination with standard chemotherapeutic agents, best tumor types to be targeted, and demonstration of cdk modulation from tumor samples from patients in these trials are important questions that need to be answered to advance these agents to the clinic.
Treatment of chronic lymphocytic leukemia has greatly advanced in the past few years since introduction of the fludarabine/cyclosphosphamide/rituximab regimen as first-line therapy. Nevertheless, 17p deletion represents a challenge because conventional treatment does not provide satisfactory results. 17p deletion and TP53 mutation are the major factors accounting for rapid disease progression, poor response to therapy, early relapse, and short survival. Allogeneic stem cell transplantation harbors curative potential but also considerable morbidity and mortality. Novel agents acting independently of the p53 signaling pathway, with favorable side-effect profiles, are promising. This review summarizes up-to-date knowledge about 17p deletion and the spectrum of treatment options.
Today, lung cancer represents a major public health concern worldwide, accounting for about 12% of all new cancers in both sexes . Small cell lung cancer (SCLC), accounting for 20% to 25% of all lung cancers, is highly sensitive to chemotherapy and radiotherapy. Optimal treatment yields a high response rate (60%-90%), but most patients relapse and will eventually die of chemotherapy-resistant disease . SCLC, however, is potentially curable, with a 5-year survival rate of 7% to 15% in limited-stage disease (LD) . The recognition of prognostic factors in SCLC has several aims including the following: 1. Individual prognostic counseling 2. Selecting treatment, when therapeutic options depend on the baseline clinical characteristics of the subject 3. Adjusting for inhomogeneities when comparing groups of patients from different locations and studies 4. Defining the eligibility criteria for new clinical trials and stratifying patients by risk subgroups 5. Understanding certain factors that may provide insights into the disease process and provide direction for further studies Although some of these reasons may appear rather theoretic, they do have practical relevance. As for many other solid tumors, the variability in prognosis among SCLC patients is more substantial than improvements in prognosis due to therapy. The failure to appreciate adequately the importance of prognostic factors may contribute to the design of inefficient studies, the erroneous interpretation of results, and the development of an inconsistent literature. A recent development of the research on prognostic factors has been made possible by the widespread use of data-recording systems based on microcomputers. Single institutions are now able to analyze their own data or to cumulate them into large multi-institutional files by exchanging magnetic support media. As a result, the number of studies dealing with newer and more traditional prognostic factors is proliferating. A MEDLINE search using the terms prognostic factor and cancer produced 2393 articles, according to a recent editorial . It is unfortunate that the interpretation of this vast and ever-growing literature is not easy . Apart from the magnitude itself of the relevant literature, there is a remarkable inhomogeneity among studies. Major differences concern the following: 1. Study populations (eg, LD and extensive disease [ED]) 2. Diagnostic criteria and treatment modalities 3. Statistical analysis (eg, the univariate survival estimate of Kaplan-Meyer, the multivariate Cox logistic regression, and the recursive partitioning and amalgamation algorithms [RECPAM]) 4. The mix of variables that are taken into consideration 5. The inclusion of post-treatment factors such as response to treatment 6. The endpoints themselves (eg, the entire survival curve or the survival at particular times, usually survival rates at 2 or 5 years) Traditionally, the anatomic extent of disease, performance status (PS), and weight loss (WL) have been used to predict the outcome of patients with SCLC [5-10]; however, simple biochemical tests and serum tumor markers are also predictive of survival. A multiple regression analysis identified PS, disease extent, AP, sodium, and albumin as contributing independently to survival. Using these parameters, three prognostic groupings could be defined. The patients in the "best" prognostic group were found to have higher response to treatment and longer survival times . In 407 SCLC patients, 61 pretreatment variables were evaluated in a Cox multiple regression analysis by Cerny and coworkers [ 16]. LDH (P = 0.001), tumor stage (P = 0.0001), serum sodium (P = 0.0009), pretreatment KPS (P = 0.0121), AP (P = 0.0186), and serum bicarbonate (P = 0.0321), but not albumin, were significant prognostic factors . The study reported by the Subcommittee for the Management of Lung Cancer (United Kingdom Coordinating Committee on Cancer Research) merits mentioning . This study collected information from 10 different British SCLC studies on 17 laboratory tests and nearly 4000 patients and concluded that the most useful laboratory tests are AP, glutamic oxalacetic transaminase, LDH, and sodium . In the opinion of the subcommittee, these parameters should be measured in any future SCLC study . Recently, hemoglobin, leukocyte, and platelet counts were found to be independent prognostic factors in 436 patients included in a prospective multicenter SCLC study with a minimum of 5-year follow-up .
Chronic myeloid leukemia (CML) is caused by the Bcr-Abl oncoprotein,the product of the t(9;22) chromosomal translocation that generates the Philadelphia chromosome. Different disease phenotypes are associated with each of the three Bcr-Abl isoforms: p190Bcr-Abl, p210Bcr-Abl, and p230Bcr-Abl all of which have a constitutively activated tyrosine kinase. Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signaling pathways, inhibition of apoptosis, and proteasomal degradation of physiologically important cellular proteins.CML is subject to an inexorable progression from an "indolent" chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.
As advances in cancer medicine turn this once uniformly fatal illness into a curable disease for growing numbers and a chronic illness for many, understanding and meeting the needs of long-term cancer survivors and their caregivers has become a major public health challenge, a challenge made more urgent by the aging of the population. This article reviews the profile of today's cancer survivors along with the demographic information on what this profile might look like in the future. Current directions in and the knowledge gained from the growing body of cancer survivorship research and the science of the long-term and late consequences to individuals, families, and society of people living longer with a cancer history are delineated.
[(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is currently the most accurate and reliable tool for the assessment of response in Hodgkin's lymphoma (HL). FDG-PET is superior to conventional imaging techniques for detection of residual disease at the end of treatment, especially in the presence of a residual mass, a frequent finding in HL. FDG-PET response assessment has also a high predictive value early after the initiation of therapy. However, whether risk-adapted treatment strategies based on FDG-PET may also improve patient outcome remains to be proved.
Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is the most accurate tool for staging, treatment monitoring, and response evaluation in Hodgkin lymphoma (HL). Early determination of treatment sensitivity by FDG-PET is the best tool to guide individualized, response-adapted treatment. Several ongoing or recently completed trials have investigated the use of FDG-PET/CT for early response-adapted HL therapy. The results are encouraging, but the data are immature, and PET response-adapted HL therapy is discouraged outside the setting of clinical trials. PET/CT looks promising for selection of therapy in relapsed and refractory disease, but the role in this setting is still unclear.
The authors propose that hemostasis occurs in a stepwise process, regulated by cellular components in vivo. The effectiveness of hemostasis in vivo depends not only on the procoagulant reactions but also on the fibrinolytic process. Causes of coagulopathic bleeding include consumption of coagulation factors and platelets, excessive fibrinolysis, hypothermia, and acidosis. Generation of the right amount of thrombin during the coagulation process not only may be essential for effective hemostasis but also may set the stage for effective wound healing.
Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for patients with advanced renal cell carcinoma (RCC). Although the next few years may not see such broad paradigm shifts, there remains significant room for improvement in the care of patients with RCC. This review discusses challenges that face physicians and researchers as well as innovations that may contribute to improving the therapeutic outcomes for patients with RCC.
B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy.
Significant progress has been made in the last 10 years on the identification of histologic parameters that are independent predictors of melanoma prognosis, immunohistochemical markers of cells of melanocytic origin and changes in adhesion molecules, cytoskeletal proteins, growth factor receptors, cell signaling, and nuclear proliferation proteins associated with tumor progression. Histologic criteria may never be completely sufficient to predict behavior accurately, because the fundamental change that renders a cell aggressive may not be morphologically reflected and may require immunohistochemical or other molecular markers to establish behavior. To date, it is humbling that no immunohistochemical or molecular marker provides a greater predictable value for aggressive behavior than does the simple calibrated ocular micrometer to measure tumor thickness. Nevertheless, development of multiple histologic parameters with the concept of nontumorigenic RGP and tumorigenic VGP provides a reliable statistical model to predict metastases. Fortunately, nontumorigenic RGP melanomas with greater than 75% regression are rare. Thus, individual patients with melanoma without regression and without the tumorigenic VGP can be given reasonable assurance of 100% survival. Nevertheless, this assurance is based on a statistical model with a finite population studied. Additional studies are needed to confirm this model, as well as more definitive markers to precisely predict outcome for those individuals with tumorigenic VGP melanoma.
The French protocol LALA 87 was designed to compare three different postinduction strategies in adult acute lymphocytic leukemia (ALL): chemotherapy, autologous transplantation, and allogeneic transplantation. This trial demonstrated a significant superiority of allogeneic bone marrow transplantation (BMT) in high-risk ALL patients. Similarly, there was a trend in favor of autologous BMT over chemotherapy in those same patients. Allogeneic BMT was not superior to autologous BMT or chemotherapy in less aggressive leukemia (standard-risk ALL). Further improvements are warranted in the treatment of adult ALL. The authors' current ongoing study is stratifying patients to allocate them to regimens with risk-adapted treatment intensity.
A technetium-labeled monoclonal antibody was administered to 52 patients with non-small cell lung carcinoma, either to stage the mediastinum preoperatively or to detect distant metastases. Results from planar and tomographic imaging are compared to CT and histologic confirmation. Differences in detection rates and predictive values between imaging modalities are discussed. The authors conclude that imaging with a technetium-labeled monoclonal antibody is safe and accurate and may be useful for staging patients with either operable or inoperable non-small cell lung cancer.
Cytochrome b-245 is an integral, and probably the terminal, component of the microbicidal oxidase electron transport chain of phagocytic cells. Current knowledge of the biochemistry and cell and molecular biology of this molecule is described. The molecular basis of chronic granulomatous disease, in which defective electron transport down this chain predisposes to infection and impaired digestion by phagocytes, is explained in terms of anomalies of the cytochrome b and related molecules.
Recurrent colorectal carcinoma constitutes a major health care problem, with 90,000 patients diagnosed annually with metastatic disease. Recent advances have offered treatment to selected patients with liver, lung, and intra-abdominal metastases. Resection of liver secondary tumors improves 5-year survival from 0% to approximately 30% and offers the only possibility for cure. As experience mounts, hepatic surgery can be performed with quite acceptable morbidity and mortality. Adjuvant therapies are being developed that may improve results with surgery alone. Cryoablation is a new technique that appears to effectively eradicate liver tumors, but its role remains to be defined. In patients with unresectable disease, the benefit of hepatic artery infusion of chemotherapy is unproven. Resection of pulmonary metastases significantly improves survival in patients with solitary nodules. Consistent data regarding the benefit of pulmonary metastatectomy in patients with multiple nodules are not available. Combined cytoreductive surgery and intraperitoneal hyperthermic chemotherapy is being investigated as a treatment for peritoneal carcinomatosis from colorectal cancer. Although selected patients may benefit, this combined treatment modality appears to be less effective in patients with colorectal cancer than with other types of cancer.
From August 1981 to December 1986, 47 patients with endometrial cancer, surgical stage I through IV, received adjuvant whole abdominopelvic irradiation with a nodal and vaginal boost. Median age was 66.5 years (range: 37 to 86 years). Twenty-two patients were stages I-II and 25 patients were stages III-IV. Thirty-four patients (79 per cent) had positive peritoneal cytology, 29 patients (62 per cent) had deep myometrial involvement, 27 patients (58 per cent) had high-grade lesions, 18 patients (40 per cent) had either serous-papillary or adenosquamous histologic variants, and 10 patients (22 per cent) had residual disease of up to 2 cm remaining after operation, mostly in the form of nodal disease. Twenty-four patients (51 per cent) have had two or more laparotomies. Mean follow-up was 40.5 months (range: 17 to 81 months). The 5-year overall survival rate was 66 per cent, and the 5-year relapse-free survival rate was 77 per cent. Toxicity has been modest, usually of the acute type, and particularly evident in thin patients (weight below 115 pounds).
Molecular characterization of chromosomal aberrations in non-Hodgkin's lymphoma (NHL) has provided a basic understanding of mechanisms of oncogene deregulation. Cytogenetic aberrations have been correlated with histologic subtype, immunophenotype, and clinical features of NHL. Although the incomplete specificity of some of the observed associations may limit the routine use of these markers in a clinical setting, the utilization of cytogenetic analysis can contribute to the diagnosis and management of patients with NHL.
The advent of imatinib has been a major breakthrough in chronic myeloid leukemia (CML) treatment. A few patients treated with imatinib are either refractory to imatinib or eventually relapse. Resistance is frequently associated with mutations in the kinase domain of BCR-ABL. Over 100 point mutations coding for single amino acid substitutions in the BCR-ABL kinase domain have been isolated from CML patients resistant to imatinib treatment. Most reported mutants are rare, whereas 7 mutated residues comprise two-thirds of all mutations detected. BCR-ABL mutations affect amino acids involved in imatinib binding or in regulatory regions of the BCR-ABL kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. The early detection of BCR-ABL mutants during therapy may aid in risk stratification as well as molecularly based treatment decisions.
The 5-year results of neoadjuvant androgen suppression and external beam radiation therapy for locally advanced prostate cancer show a benefit in local, distant, and biochemical control when compared with external beam radiation therapy alone. Further follow-up will ascertain if these findings translate into a survival benefit. Combined modality staging is a methodology in which all of the pretreatment clinical factors that are found to have independent prognostic significance on multivariable analysis for predicting a given outcome (for example, pathologic stage) are used to determine the initial management. This method of staging is able to provide an optimized assessment of the pathologic extent of local disease prior to management, and therefore it is better able to define those patients in whom local-only therapy is likely to be curative. Knowing more reliably the pathologic extent of disease prior to therapy also provides a rationale for patient selection in clinical trials that are currently testing the impact on overall survival of combining androgen suppression and external beam radiation therapy for early stage (T1b-T2b) prostate cancer.
β-Thalassemia is a genetic disorder caused by mutations in the β-globin gene and characterized by chronic anemia caused by ineffective erythropoiesis, and accompanied by a variety of serious secondary complications such as extramedullary hematopoiesis, splenomegaly, and iron overload. In the past few years, numerous studies have shown that such secondary disease conditions have a genetic basis caused by the abnormal expression of genes with a role in controlling erythropoiesis and iron metabolism. In this article, the most recent discoveries related to the mechanism(s) responsible for anemia/ineffective erythropoiesis and iron overload are discussed in detail. Particular attention is paid to the pathway(s) controlling the expression of hepcidin, which is the main regulator of iron metabolism, and the Epo/EpoR/Jak2/Stat5 signaling pathway, which regulates erythropoiesis. Better understanding of how these pathways function and are altered in β-thalassemia has revealed several possibilities for development of new therapeutic approaches to treat of the complications of this disease.
Renal diseases are associated with a host of hematologic abnormalities affecting erythropoiesis, thrombopoiesis, platelet function, coagulation, fibrinolysis, and immune function. Many of the abnormalities described in acute or chronic renal failure appear to be directly related to accumulation of uremic toxins, particularly those in the middle molecular range and may respond to dialysis treatment. The recent availability of recombinant human erythropoietin facilitated the demonstration that anemia in renal failure is predominantly due to inadequate production of erythropoietin, and evolution in the management of anemia in these patients is now likely. Renal cell carcinoma is associated with a variety of unusual hematologic manifestations that may be confused with other diseases, but when recognized provide an early clue to the presence of a renal tumor and result in successful therapy.
Hemostasis is intimately related to liver function, because most coagulation factors are synthesized by liver parenchymal cells and the liver's reticuloendothelial system serves an important role in the clearance of activation products. The extent of coagulation abnormalities depends upon the degree of disturbed liver function. Acute or chronic hepatocellular diseases may display decreases in the vitamin K-dependent factors (prothrombin; factors VII, IX, and X; proteins C and S), whereas other parameters remain normal. Patients with hepatic failure may present with the entire spectrum of factor deficiencies and may even develop disseminated intravascular coagulation (DIC). Patients with liver cirrhosis have a wide spectrum of abnormalities. Except for factor VIII:C and von Willebrand factor, all procoagulant and inhibitory factors are decreased, which is a reflection of impaired protein synthesis. Abnormal fibrinogen and prothrombin molecules can be identified. Platelets are quantitatively and qualitatively altered, and most patients develop DIC. Vitamin K deficiency leads to the production of abnormal vitamin K-dependent factors. The factors lack gamma-carboxy glutamic acid residues in the NH2-terminal part of their molecules. Surgery associated with the liver leads to major hemostasis alterations. The LeVeen shunt is invariably related to DIC. Bleeding with partial liver resection is mostly mechanically induced, but chronic DIC may be present. Orthotoptic liver transplantation is associated with severe hemorrhages. These are partly due to the pre-existing hemostasis defects and partly due to DIC with a marked fibrinolytic response. This is especially noted during the anhepatic phase and when the donor liver is perfused by the recipient's blood. Postoperative recovery is quick, provided the graft is not rejected. Postoperatively, there may be an initial hypercoagulable state, which could be related to the thrombosis occasionally encountered.
The last 3 decades have seen much progress in the treatment and outcome of patients with ALL. Unfortunately, the success that has been achieved in children with ALL has not yet been translated into adult patients. Insight into the biologic and molecular abnormalities in ALL may, however, provide the necessary clues that allow a clearer understanding of the crucial differences in the behavior of ALL in different groups of patients. As the molecular basis of the disease is deciphered, new targets are discovered that may prove useful for therapeutic interventions in the future.
A wide variety of endocrine disorders can be associated with hematologic dysfunction. Usually the hematologic manifestations of endocrine disease are mild to moderate and self-limited. Correction of the endocrinopathy should result in clearing of the hematologic disturbance. Whereas it is prudent to recognize the impact of endocrinology on red cell, leukocyte, platelet, and coagulation physiology, serious hematologic disorders are usually not solely the result of endocrinopathies but are instead associated or coincident abnormalities. There are some situations (e.g., the coagulopathies associated with Cushing's syndrome, oral contraceptive use, or hypothyroidism) in which an appreciation of the attendant hematologic abnormalities may prompt preventative actions.
In myelodysplastic syndromes, several autoimmune phenomena are more common than expected. Lymphocyte subsets are sometimes abnormal in number and function. Associated lymphoid malignancies and lymphoblastic evolution have occasionally been reported. Molecular studies suggest that the lymphoid system may be involved in the dysplastic process.
Hematologic abnormalities are not uncommon in patients with nonhematologic malignancies and may contribute significantly to morbidity and even to mortality. An appreciation for the spectrum of severity and etiology will allow the physician to anticipate and perhaps ameliorate some of these complications. This understanding will also provide sufficient information to decide when intervention is unnecessary.
The hematologic manifestations of HIV infection include morphologic abnormalities of peripheral blood and bone marrow changes. Laboratory abnormalities, including measures of coagulation, serum vitamin B12 levels, and positive Coombs's test, are seen with HIV infection and may not carry the same clinical consequence as when noted in non-HIV infected populations. Antibodies to circulating red blood cells, platelets, and granulocytes may represent alterations in autoimmunity or nonspecific HIV-induced B-cell stimulation, but they do not necessarily correlate with development of peripheral blood cytopenias. The advent of commercially available hematopoietic growth factors has allowed greater insight into specific host-virus-drug interactions that may be important in regulating viral growth and expression. Novel clinical approaches using hematopoietins alone or in combination with antimicrobial, antiviral, and antitumor drugs represent exciting developments in the treatment of HIV infection.
Hemostatic abnormalities are prominent and enigmatic features of HIV infection. In the foregoing discussion, many questions have been raised about the pathogenesis and treatment of HIV-related ITP, TTP, and ACA. The mechanism of platelet destruction in HIV-infected patients remains poorly defined, and the way in which HIV triggers these hemostatic abnormalities is unknown. Treatment of patients in the shadow of AIDS also poses unique problems for the clinician. Nevertheless, HIV-related thrombocytopenia provides a model for other forms of immune cytopenias, and better understanding of this form of ITP will lead to improved treatment modalities for other autoimmune diseases. Conversely, HIV-related ITP, TTP, and ACA should be viewed as part of a spectrum of autoimmune processes triggered by HIV. By defining the significance of these autoimmune processes in AIDS, more effective approaches to the treatment of HIV disease can and will be developed.
In the hematologic malignant diseases, specific cytogenetic abnormalities correlate with clinical, morphologic, and immunophenotypic features. Although relatively little is known regarding the karyotypic pattern of Hodgkin's disease, it is clear that the involvement of specific chromosomes in numerical and structural abnormalities is nonrandom. Hyperdiploidy is a characteristic feature of Hodgkin's disease and is observed in 70 per cent of tumors that have an abnormal karyotype. A gain of chromosomes 1, 2, 5, 12, and 21 is a recurring numerical abnormality; structural rearrangements involving chromosome 1 are frequently observed. Perhaps as a result of the relatively small number of cases that have been analyzed, recurring structural abnormalities have not yet been identified; it has also not been possible to determine whether the various histologic subtypes of Hodgkin's disease are characterized by unique abnormalities. The prognostic significance of cytogenetic abnormalities in Hodgkin's disease is unclear; however, preliminary results suggest that the karyotype may have prognostic importance in this disease. The correlation of the cytogenetic pattern with the clinical and morphologic features will be essential in evaluating the clinical and biologic significance of chromosomal abnormalities in Hodgkin's disease.
Patients with multiple myeloma, Waldenström's macroglobulinemia, benign monoclonal gammopathy, and other B-cell disorders associated with high titer serum paraproteins can manifest unique hemostatic disorders. Most of these disorders predispose the patient to hemorrhage, especially following surgical procedures. Mechanisms can include: acquired von Willebrand syndrome, paraprotein-induced platelet function defects, factor X deficiency, and local tissue fragility associated with amyloidosis, abnormalities of the function of fibrin, circulating anticoagulants, and thrombocytopenia. The mainstay of therapy is the treatment of the underlying disease. Depending on clinical circumstances, additional therapies might include: plasmapheresis with appropriate factor replacement, arginine vasopressin, fibrinolysis inhibitors, and splenectomy. Less commonly, the paraprotein disorders are associated with thrombotic complications, especially in those cases in which the lupus anticoagulant is present.
There is an increasing understanding that chromosomal abnormalities play a major role in the pathogenesis of multiple myeloma. Furthermore, they seem to predict the clinical outcome of patients according to the specific abnormalities detected. It is likely that in the future, knowledge of the cytogenetic composition will be an integral part of the evaluation of myeloma patients.
The progressive decline in the number and function of circulating CD4+ T lymphocytes remains the most characteristic immunologic abnormality found in persons infected with HIV. With the CD4+ cell as the central element in the immunologic cascade of events involved in antigen recognition and host defense, loss of normal CD4 number and function results in impairment of many immune functions that require induction signals by CD4 lymphocytes, including CD8 function, B lymphocyte production of immunoglobulin, NK cell function, and monocyte/macrophage function. Although CD4 cell depletion is a major factor in the pathogenesis of HIV infection, immunologic abnormalities such as impairment of responses to soluble protein antigens appear even before detectable loss of circulating CD4 cells. Progression of clinical disease occurs despite the development of antibodies to HIV proteins. Cellular immune responses have been described in a limited number of individuals, but their exact role is not yet understood. Delineation of the precise nature of the immunologic defects in HIV infection should provide the basis for the continued development of better therapeutic strategies.
The chromosomal abnormalities that occur in acute lymphoblastic leukemia have greatly elucidated the biologic causes (leukemogenesis) of this disease. ALL is extremely heterogeneous; different cell types at differing stages of differentiation may become leukemic. Although not yet completely understood, the chromosomal abnormalities occurring in this disease are not random. Rather, the abnormalities are highly specific, with specific abnormalities occurring in specific cell phenotypes. Early chromosomal investigations were concerned with identification of heterogeneous cytogenetic "groups," with independent prognostic indications, among patients with ALL. These studies progressed to the identification of specific chromosomal translocations, many of which can be correlated with specific cell phenotypes. Molecular studies of these cytogenetic aberrations have defined specific chromosomal breakpoints, and specific genes, which have been implicated in the oncogenic process. As a result of these translocations, the involved genes either produce abnormal products or are deregulated. The products of these genes vary, but all are concerned with cell growth and differentiation. Much remains to be determined regarding cytogenetic abnormalities in acute lymphoblastic leukemia and their clinical and biologic significance. The molecular bases of all of the recurring abnormalities in ALL have not been determined. The biologic causes for the chromosomal abnormalities are not known, nor is it known why specific chromosomal aberrations correlate with prognosis.
In 1869, Nettleship and Tay(159) described a 2-year-old child with hyperpigmented, urticarial skin lesions. Their report is credited as being the first description of urticaria pigmentosa. It was not until 1877(54) that mast cells were first described by Ehrlich, who found cells possessing cytoplasmic granules that stained metachromatically with aniline dyes. He called these cells "mastzellen" because they were distended with granules. Subsequently, in 1878, Sangster(191) described a patient with a pigmented, urticarial rash which he called "urticaria pigmentosa." In 1887,(226) Unna demonstrated the presence of mast cells in the skin lesions of affected patients. It was not until 50 years later, in 1933, that Touraine and co-workers(217) suggested that the disease might involve internal organs and 16 years later, in 1949, that Ellis et al(55) established this fact on an autopsy study in a 1-year-old child. In this first description of systemic mastocytosis by Ellis et al(55) the patient had urticaria pigmentosa from birth and developed diarrhea with voluminous, foul-smelling stools. Autopsy revealed hepatomegaly, splenomegaly, and lymphadenopathy, with microscopic infiltration by mast cells of the bone marrow, liver, spleen, lymph node, kidney, and pancreas.(55) Therefore, in both the clinical description and histologically, there was clear evidence for gastrointestinal involvement in the first established case of systemic mastocytosis.(55) In 1936, Sezary(200) proposed the name mastocytosis for this generalized involvement by mast cells.
Once considered exceptionally rare, congenital thrombocytopenias are increasingly recognized as a heterogeneous group of disorders characterized by a reduction in platelet number and a bleeding tendency that may range from very mild to life threatening. Although some of these disorders affect only megakaryocytes and platelets, others involve different cell types and may result in characteristic phenotypic abnormalities. This review elaborates the clinical presentation and laboratory manifestations of common congenital thrombocytopenias in addition to exploring our understanding of the molecular basis of these disorders and therapeutic interventions available.
Thrombocytopenia is a relatively common clinical problem in hospitalized neonates, and it is critical to distinguish infants who have rare congenital thrombocytopenias from those who have acquired disorders. Two well-described inherited thrombocytopenia syndromes that present in the newborn period are congenital amegakaryocytic thrombocytopenia (CAMT) and thrombocytopenia with absent radii (TAR). Although both are characterized by severe (< 50,000/microL) thrombocytopenia at birth, the molecular mechanisms underlying these disorders and their clinical presentations and courses are distinct. CAMT is an autosomal recessive disorder caused by mutations in the thrombopoietin (TPO) receptor c-Mpl. TAR is a syndrome of variable inheritance and unclear genetic etiology consisting of thrombocytopenia in association with bilateral absent radii and frequently additional congenital abnormalities. This article summarizes the current understanding of the pathophysiology and clinical course of CAMT and TAR.
It appears that the government is taking a no-holds-barred type approach to combating fraud and abuse of government programs by enacting new and by expanding existing statutes designed for this purpose. It is clear now, more than ever, that due to the abuse suffered by federal health care programs, the government, by and through its respective agencies, is using every resource available to track, identify, and prosecute those who defraud and attempt to defraud these programs. It is therefore imperative that hospitals and health care professionals take the necessary precautions to ensure that inadvertent violations of these statutes do not occur.
Alcoholism affects 3 to 10 per cent of the population and costs Americans about $60 billion a year. The disease can be identified in from 19 to 25 per cent of hospital admissions. It is responsible for almost 10 per cent of direct health care costs and more than 200,000 deaths annually. Increased attention to alcoholism has allowed the development of sensitive historic means by which a diagnosis can be established earlier in its natural course. Unfortunately, laboratory abnormalities appear late, long after dependence/addiction is well established. Ethanol is toxic to all organs. Adverse hematopoietic effects result from direct toxicity to the bone marrow and indirectly from other metabolic derangements. Since normal function of the hematopoietic system is dependent on the coordinated interplay of many other systems, it is not surprising that ethanol's effects on the blood may be multiple, complex, and highly variable. This review summarizes current information about the hematologic sequela of alcohol abuse. An introductory overview of ethanol-related metabolic events is followed by discussions of specific disorders of erythrocytes, leukocytes, platelets, and the immune apparatus.
The goal of therapy for patients with advanced-stage Hodgkin lymphoma is to ensure that as many patients as possible are healthy and free of disease decades after completing treatment. To achieve this, the treating physician needs to select the most effective therapeutic regimen, but also needs to choose a treatment strategy that limits long-term toxicity. One approach to achieve this is to use a less intense combination, such as ABVD chemotherapy, as initial treatment and intensify therapy only in those patients who do not become PET negative or who subsequently relapse.
Chronic myelogenous leukemia (CML) may have a biphasic or triphasic course, whereby patients who were initially diagnosed in the chronic phase (CP) develop more aggressive disease, frequently pass through an intermediate or accelerated phase (AP), and finally evolve into an acute leukemia like blastic phase (BP). A slowing in the rate of development of AP or BP has accompanied successive improvements in therapy for patients who have CP CML. Variable diagnostic criteria for AP and BP are used in the literature, rendering comparisons difficult. The management of patients in AP or BP consistently has been less effective than the management of those inCP for all modalities of therapy. This article reviews the current diagnostic criteria, therapeutic strategies, outcomes, and investigational therapies for AP and BP CML.
Much work has been done regarding QOL in lung cancer trials. There are now several validated QOL instruments, particularly for patients with lung cancer. Past accomplishments include key trials demonstrating a benefit of chemotherapy or radiation in patients with advanced NSCLC not only regarding traditional endpoints but also by improving palliation and aspects of QOL such as pain and dyspnea. More recently, studies have emerged that incorporate QOL in patients with locally advanced disease. Key challenges relate to the optimal design and successful completion of these QOL studies. Missing data remains a key problem in many QOL studies, particularly in lung cancer trials. Future studies should focus on incorporating QOL into phase III studies with clear hypotheses that can ultimately lead to clinically meaningful interventions.
In comparison to past decades, children who have acquired aplastic anemia (AA) enjoy excellent overall survival that reflects improvements in supportive care, more accurate exclusion of children who have alternate diagnoses, and advances in transplantation and immunosuppressive therapy (IST). Matched sibling-donor hematopoietic stem cell transplants (HSCT) routinely provide long-term survival in the range of 90%, and 75% of patients respond to IST. In this latter group, the barriers to overall and complication-free survival include recurrence of AA, clonal evolution with transformation to myelodysplasia/acute myelogenous leukemia, and therapy-related toxicities. Improvements in predicting responses to IST, in alternative-donor HSCT, and in rationalizing therapy by understanding the pathophysiology in individual patients are likely to improve short- and long-term outcomes for these children.
Platelet dysfunctions, especially acquired forms, are common causes of hemorrhage, especially when associated with trauma or surgery. Although the hereditary platelet function defects are generally quite rare, hereditary storage-pool disease is common enough to be suspected in an individual, usually a child, with characteristic historical and clinical findings. The acquired platelet function defects, especially those resulting from drugs, are very common and should promptly be suspected in patients developing easy and spontaneous bruising, mild to moderate mucosal membrane hemorrhage, or unexplained bleeding associated with trauma or surgery. The template bleeding time is generally useful as a screening test of platelet function, but a normal template bleeding time, in the face of a suggestive history, suggestive clinical findings, or in the patient frankly bleeding, is not reliable, and platelet aggregation or lumi-aggregation should be done in appropriate clinical situations. Also, prolongation of the template bleeding time is an unreliable predictor of clinical bleeding propensity. The mainstay of therapy for essentially all these defects, if bleeding is significant, is the liberal infusion of appropriate numbers of platelet concentrates. The acquired platelet function defects should also be managed by attempts to treat or control the underlying disease, if possible, and offending drugs or potentially offending drugs should immediately be stopped.
The current status of knowledge of the uremic hemorrhagic diathesis is reviewed. Discussions of clinical features, classification and pathogenesis, retention products and hemostatic defects, and therapy are included.
Franconi's syndrome is a rare complication of the monoclonal gammopathies characterized by diffuse failure in reabsorption at the level of the proximal renal tubule resulting in glycosuria, generalized aminoaciduria, and hypophosphatemia. Current evidence suggests monoclonal light chains that are incompletely digested in renal tubule lysosomes cause renal injury. The light-chain fragments serve as a nidus for crystal formation, and the crystals interfere with a broad range of apical membrane transporters. Franconi's syndrome is predominantly associated with monoclonal kappa in the urine, but rare instances of FS caused by lambda light chains have been described. Overt hematologic malignancies such as multiple myeloma, Waldenström's macroglobulinemia, or other lymphoproliferative disorders occur in one third of patients. Clinical manifestations include slowly progressive renal failure and bone pain caused by osteomalacia. The osteomalacia is caused by chronic hypophosphatemia and may be exacerbated by secondary hyperparathyroidism and renal tubular acidosis. Treatment consists of supplementation with phosphorus, calcium, and vitamin D. The osteomalacia is often completely reversible with mineral supplementation. Patients with an associated symptomatic malignancy or rapidly progressive renal failure may also benefit from chemotherapy. The prognosis is good in the absence of overt malignant disease.